Angiogenesis is a process of forming new blood vessels from pre-existing ones, and plays an important role in normal body defense mechanisms, such as wound healing and inflammation, and physiological phenomenon and early-stage development. The angiogenesis occurs through a series of sequential steps including reconstructing vessels and generating new capillary vessels through decomposition of vascular basement membrane by proteolytic enzyme, proliferation and migration of the vascular endothelial cells that constitute vessel walls and tube (a blood-vessel) formation by differentiating the vascular endothelial cells.
In addition, the angiogenic process is strictly regulated by various negative and positive regulatory factors. However, if the angiogenic process is not regulated properly, it can accelerate various diseases including cancer, rheumathritis, or diabetic retinopathy. Abnormal angiogenesis is particularly known to play a critical role in tumor growth and metastasis; firstly, it supplies nutrients and oxygen needed for the growth and proliferation of tumor, and secondly, the new capillary vessels which invade into the tumor provide tumor cells a chance to spread to the blood circulation system, thereby enabling the tumor cells to spread all over the body.
Therefore, mechanistic studies of angiogenesis and its application in development of new inhibitors have gained increasing attention in the prevention and treatment of various diseases including cancer. In the recent years, the studies on angiogenesis inhibitor have been accelerated as the experimental animal tumor model studies and human clinical studies have confirmed that inhibition of tumor angiogenesis can effectively inhibit the growth and progress of tumors and thereby prolong patient's lifespans.
Moreover, such angiogenesis inhibitor is particularly considered to be promising in the anticancer therapy, because, firstly, the angiogenesis inhibitor can be used universally in all types of solid tumors, secondly, while the conventional anticancer chemo-therapy has toxicity on the bone marrow cells and stomach system cells with relatively faster cell cycle due to its principle of using fast growth of cancer cells, the angiogenesis inhibitor has relatively less side effects even for a long period of administration, thirdly, it is possible to suppress many cancer cells through inhibition of one blood vessel cell, because one vessel cell can supply nutrients and oxygen to hundreds of cancer cells, and fourthly, while anticancer agents have to move out of the vessel to affect cancer cells, the angiogenesis inhibitor directly contacts and acts on the endothelial cells without additional drug delivery.
Meanwhile, approximately 200 angiogenesis inhibitors have been developed so far, which can be mainly characterized into four mechanisms of: lowering activity of a specific vascular growth factor; suppressing growth or inducing death of vascular endothelial cells; suppressing the vascular growth factor or the action of indirect factors that regulate the endothelial cell survival factors; and increasing the activity of the angiogenesis inhibitor present in body. The angiogenesis inhibitors such as angiostatin, endostatin, PK5, and prothrombinkringle 2 are particularly widely known.
However, since most angiogenesis inhibitors developed so far are in the form of compounds or proteins, there are disadvantages in that it is difficult to maintain these inhibitors' good activity for a long period of time and mass-produce these inhibitors, and also a process of producing these inhibitors costs a lot. In addition, there are disadvantages in that pharmaceutical properties of these inhibitors are low, and these inhibitors may be easily denaturated.
Therefore, attempts have been recently made to develop an angiogenesis inhibitor in a peptide form to overcome the problems as described above, since peptides can be used as an effective angiogenesis inhibitor due to its molecular characteristics, such as longer plasma half-life, high resistance to degradation, high bioavaiability and excellent affinity in vivo. Among the related prior arts, Korean Patent Publication No. 2005-0097494 discloses peptide for inhibiting angiogenesis, cell migration, cell invasion and proliferation and a composition comprising such peptide, and Korean Patent Registration No. 0274172 discloses TIMP-2 derived synthetic peptide for inhibiting angiogenesis by inhibiting activity of type IV collagenase.
However, since the conventionally available angiogenic-inhibiting peptide needs more improvement in the anti-angiogenic activity effect, development of new peptides for potent angiogenesis inhibition is necessary.